Pharmacologically active compounds

ABSTRACT

Heterocyclic compounds which are inhibitors of histamine activity, in particular, inhibitors of H-2 histamine receptors. A specific compound of this invention is 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone.

This is a division of application Ser. No. 485,535, now U.S. Pat. No.4,470,985 filed Apr. 15, 1983, which is a division of Ser. No. 364,134filed Mar. 31, 1982 now U.S. Pat. No. 4,399,142, which is a division ofSer. No. 239,238 filed Mar. 3, 1981 now U.S. Pat. No. 4,341,787, whichis a division of Ser. No. 60,324 filed July 25, 1979 now U.S. Pat. No.4,282,221, which is a division of Ser. No. 893,859 filed Apr. 6, 1978now U.S. Pat. No. 4,181,730, which is a division of Ser. No. 736,662filed Oct. 29, 1976 now U.S. Pat. No. 4,104,381, which is a division ofSer. No. 619,985 filed Oct. 6, 1975 now U.S. Pat. No. 4,005,205, whichis a division of Ser. No. 463,647 filed Apr. 24, 1974 now U.S. Pat. No.3,932,644.

This invention relates to pharmacologically active compounds andpharmaceutical compositions and methods of inhibiting H-2 histaminereceptors with these compounds. The compounds of the invention can existas the addition salts but, for convenience, reference will be madethroughout this specification to the parent compounds.

It has long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated as H-1. A further group of substances hasrecently been described by Black et. at. (Nature 1972, 236, 385) whichare distinguished by the fact that they act at histamine receptors otherthan the H-1 receptor and these other receptors have been designated asH-2 receptors. This latter group of substances, to certain of which thepresent invention relates, are thus of utility in inhibiting certainactions of histamine which are not inhibited by the above mentioned"antihistamines". The substances of this invention may also be ofutility as inhibitors of certain actions of gastrin.

Black et al., cited above, page 390, column 2, state the following:"Mepyramine has been defined as an H₁ -receptor antagonist¹ andburimamide has now been defined as an H₂ -receptor antagonist. Usedalone, burimamide can antagonize those responses to histamine, such asstimulation of acid gastric secretion, which cannot be blocked bymepyramine; histamine apparently activates H₂ -receptors to producethese effects." Thus, from the Black et al. paper, H-2 histaminereceptors are those histamine receptors which are not inhibited bymepyramine but are inhibited by burimamide.

Throughout the present specification, by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms.

The compounds with which the present invention is concerned may berepresented by the following general formula; ##STR1## wherein A takentogether with the nitrogen and carbon atoms shown forms a pyrimidine,imidazoline, quinazoline, pyridine, benzothiadiazine, 1,2,4-thiadiazine,thiazoline, 1,2,4-triazine or quinoline ring, said ring having a keto,thione or sulfone group and optionally substituted by one or two loweralkyl, phenyl or benzyl groups; R is a grouping of the structure shownin Formula II;

    Het--CH.sub.2 Z(CH.sub.2).sub.n --                         FORMULA II

wherein Het is a nitrogen containing heterocyclic ring such asimidazole, pyridine, thiazole, isothiazole or thiadiazole which ring isoptionally substituted by lower alkyl preferably methyl, amino, hydroxyor halogen; Z is sulphur or a methylene group; and n is 2 or 3, or apharmaceutically acceptable acid addition salt thereof.

It will be understood that, since the ring structures formed arepotentially tautomeric systems, the Formula I shown is only one ofseveral possible representations.

Particularly important classes of compounds which fall within the scopeof Formula I are the compounds of the following Formulae III to VI:##STR2## Wherein R has the same significance as in Formula I, X isoxygen or sulphur; Y₁ and Y₂, which may be the same or different, arehydrogen, lower alkyl, phenyl or benzyl or Y₁ and Y₂ together with theadjacent carbon atoms may form a phenyl ring; and Y₃ and Y₄ which may bethe same or different, are hydrogen, lower alkyl, phenyl or benzyl.

Particularly useful compounds of formulae I and III to VI are thosewherein Het is imidazole, optionally substituted by methyl. It is alsopreferred that n should be 2.

Specific compounds of this invention having advantageous utility are:

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one and

3-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide.

The compounds of the present invention may be produced by the reactionof a compound of Formula VII or of Formula VIII: ##STR3## wherein A hasthe same significance as in Formula I, B is a chain of three or fouratoms which are either all carbon atoms or which comprise a sulphurand/or one or two nitrogen atoms which chain also comprises a protectedketo or thione grouping, and Q is a reactive grouping such as halogen,methanesulphonyl, thiol or alkylthio such as methylthio with an aminocompound of formula R¹ NH₂ wherein R¹ may have the same significance asR in Formula I or may be a group such that the product from its reactionwith the compound of Formula VII or VIII may be converted by one or morereactions to a compound of Formula I.

As stated above, the compounds represented by Formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaesthetised with urethane at doses of from 2to 256 micromoles per kilogram intravenously. Similarly, the action ofthese compounds may be demonstrated by their antagonism to the effectsof histamine on other tissues which, according to the above-mentionedpaper of Black et. al., are H-2 receptors. Examples of such tissues areperfused isolated guinea-pig heart, isolated guinea-pig right atrium andisolated rat uterus. The compounds of the invention have also been foundto inhibit the secretion of gastric acid stimulated by pentagastrin orby food.

The level of activity found for the compounds of the present inventionis illustrated by the effective dose range in the anaesthetised rat, asmentioned above of from 2 to 256 micromoles per kilogram, givenintravenously. Many of the compounds of the present invention produce a50% inhibition in this test at a dose of from 5 to 20 micromoles perkilogram.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor.

Such addition salts include those with hydrochloric, hydrobromic,hydriodic, sulphuric and maleic acids and may conveniently be formedfrom the corresponding base by treatment of the latter with a dilutesolution of the appropriate acid followed by recrystallisation from asuitable solvent such as aqueous ethanol.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting H-2 histamine receptors whichcomprise administering a compound of formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 gm. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension. The pharmaceutical compositions areprepared by conventional techniques involving procedures such as mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg most preferably from about100 mg to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto three times per day. The daily dosage regimen will preferably be fromabout 150 mg to about 750 mg most preferably from about 300 mg to about600 mg.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule or injectable solution.

The invention is illustrated but in no way limited by the followingexamples:

EXAMPLE 1 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidonedihydrochloride

An intimate mixture of4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.6 g) and2-methylthio-4-pyrimidone (1.4 g) was heated to 150° over a period of 30minutes, and then at 150°-160° for 2 hours. After cooling, the reactionmixture was triturated under water to give the crude base, which wasfiltered off and dissolved in 5N hydrochloric acid. Evaporation todryness followed by recrystallisation of the residue from aqueousethanol gave2-[2-(4-methyl-5-imidazolylmethylthio)-ethylamino]-4-pyrimidonedihydrochloride (2.1 g), m.p. 246°-248°.

(Found: C, 39.25; H, 5.2; N, 20.4; S, 9.6; Cl, 20.5; C₁₁ H₁₇ Cl₂ N₅ OS;requires: C, 39.1; H, 5.1; N, 20.7; S, 9.5; Cl, 20.95).

Recrystallisation of the initial crude base from ethanol/water gave thepure base, m.p. 219°-221°.

EXAMPLE 22-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-[(2-aminoethyl)thiomethyl]-5(4)-methylimidazole (4.5g.) with 6-methyl-2-methylthio-4-pyrimidone (2.7 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-4-pyrimidonedihydrochloride, m.p. 247°-250° (ex ethanol).

(Found: C, 41.1; H, 5.7; N, 19.8; S, 8.9; Cl, 19.8; C₁₂ H₁₉ Cl₂ N₅ OS;requires: C, 40.9; H, 5.4; N, 19.9; S, 9.1; Cl, 20.1).

EXAMPLE 32-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5,6-dimethyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (4.1 g.)with 5,6-dimethyl-2-methylthio-4-pyrimidone (2.6 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-dimethyl-4-pyrimidonedihydrochloride, m.p. 235°-237° (ex methanol).

(Found: C, 42.8; H, 6.0; N, 18.7; S, 8.6; Cl, 18.8; C₁₃ H₂₁ Cl₂ N₅ OS;requires: C, 42.6; H, 5.8; N, 19.1; S, 8.75; Cl, 19.4).

EXAMPLE 4 2-[4-(4-Imidazolyl)butylamino]-4-pyrimidone dihydrochloride

Reaction of 4(5)-(4-aminobutyl)imidazole (2.1 g.) with2-methylthio-4-pyrimidone (1.4 g.) by the method described in Example 1gave 2-[4-(4-imidazolyl)butylamino]-4-pyrimidone dihydrochloride, m.p.215°-222° (ex ethanol).

(Found: C, 43.15; H, 5.6; N, 22.5; Cl, 22.8; C₁₁ H₁₇ Cl₂ N₅ O; requires:C, 43.15; H, 5.6; N, 22.9; Cl, 23.2).

EXAMPLE 54-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-thiopyrimidonedihydrochloride

A solution of 4(5)-[(2-aminoethyl)thiomethyl]-5(4)-methylimidazole (7.4g.) and 2,4-dimercaptopyrimidine (4.1 g.) in water (150 ml.) was heatedunder reflux for 12 hours. After cooling the precipitated oil wasseparated by decantation, washed with water (3×50 ml.), and dissolved in2N hydrochloric acid. The solution was evaporated to dryness and theresidue recrystallised from ethanol to give4-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-thiopyrimidonedihydrochloride, m.p. 254°-257°.

(Found: C, 37.2; H, 4.9; N, 19.7; S, 18.0; C₁₁ H₁₇ Cl₂ N₅ S₂ ; requires:C, 37.3; H, 4.8; N, 19.8; S, 18.1).

EXAMPLE 6 4-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-pyrimidone

A solution of4-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-thiopyrimidonedihydrochloride (1.0 g.) and chloracetic acid (0.35 g.) in water (5 ml.)was heated on a steam bath for 40 min. Concentrated hydrochloric acid (8ml.) was then added, the solution heated under reflux for 2 hours, andthen evaporated to dryness. The residual oil was dissolved in water (5ml.) basified with ammonium hydroxide and the precipitate washed withhot water to give4-[2-(4-methyl-5-imidazolyl-methylthio)ethylamino]-2-pyrimidone, m.p.249°-251°.

(Found: C, 49.5; H, 5.6; N, 26.3; S, 18.0; C₁₁ H₁₅ N₅ OS; requires: C,49.8; H, 5.7; N, 26.4; S, 18.1).

EXAMPLE 72-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-imidazoline-4-onedihydrochloride.

A solution of 4(5)-(2-aminoethyl)thiomethyl-5-(4)-methylimidazole (3.4g.) and 2-methylthio-2-imidazolin-4-one hydroidide (2.6 g.) in dryethanol (20 ml.) was left to stand at room temperature for 4 days. Thecrude product was filtered off, dissolved in dilute hydrochloric acidand the solution basified with aqueous potassium carbonate solution togive2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one,m.p. 224°-5° (decomp.). The dihydrochloride, m.p. 226°-228° (decomp.)was obtained by dissolving the base in dilute hydrochloric acid,evaporating to dryness and recrystallising the residue from aqueousethanol.

(Found: C, 31.1; H, 5.4; N, 21.45; S, 9.7; Cl, 21.6; C₁₀ N₁₇ Cl₂ N₅ OS;requires: C, 36.8; H, 5.25; N, 21.5; S, 9.8; Cl, 21.7).

EXAMPLE 82-[2-(4-Methyl)-5-imidazolylmethylthio)ethylamino]-4(1H)-quinazolinone

Reaction of an intimate mixture of4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.6 g.) with2-methylthio-4(1H)-quinazolinone (1.9 g.) at 120° for 41/2 hours gavethe crude base (2.7 g.) which was acidified with hydrochloric acid asdescribed in Example 1, to give, on recrystallisation fromethanol/ether,2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4(1H)-quinazolinonedihydrochloride, m.p. 249°-252°.

(Found: C, 45.8; H, 4.9; N, 17.8; S, 8.1; C₁₅ H₁₄ Cl₂ N₅ CS; requires:C, 46.4; H, 4.9; N, 18.0; S, 8.3;).

EXAMPLE 92-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-n-propyl-4-pyrimidone

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (5 g.)with 6-n-propyl-2-methylthio-4-pyrimidone (5 g.) by the method describedin Example 1 gave a hygroscopic dihydrochloride of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-6-n-propyl-4-pyrimidone,m.p. 125°-130° (crystallised from butanol/ether).

(Found: C, 44.3; H, 6.2; N, 18.3; S, 8.2; Cl, 18.7; C₁₄ H₂₃ Cl₂ N₅ OS;requires: C, 44.2; H, 6.1; N, 18.4; S, 8.4; Cl, 18.6).

EXAMPLE 102-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.0 g.)with 5-ethyl-6-methyl-2-methylthio-4-pyrimidone (1.46 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidonedihydrochloride m.p. 203°-7° (crystallised from isobutanol)

(Found: C, 43.6; H, 6.1; N, 17.9; S, 8.0; Cl, 18.5; C₁₄ H₂₃ Cl₂ N₅ O₆ ;requires: C, 44.2; H, 6.1; N, 18.5; S, 8.4; Cl, 18.6).

EXAMPLE 112-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-methyl-2-imidazolin-4-one

A solution of 5-methyl-2-thiohydantoin (15 g.) and methyl iodide (16.3g.) in dry ethanol (130 ml.) was heated under reflux for 11/2 hours, andthen allowed to stand at 0° overnight. The crystalline product wasfiltered and washed with ether to give2-methylthio-5-methyl-2-imidazolin-4-one hydroiodide (17.8 g.), m.p.170°-173°.

A solution of this hydroiodide (2.7 g.),4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.5 g.) andtriethylamine (1 g.) in dry ethanol (20 ml.) was left to stand at roomtemperature for 10 days. The resulting crude product (1.6 g., m.p. 218°)was dissolved in hydrochloric acid and the solution basified withsaturated aqueous potassium carbonate solution to give hydrated2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-methylimidazolin-4-one,m.p. 216°-220°.

(Found: C, 48.5; H, 6.4; N, 25.4; S, 11.9; C₁₁ H₁₇ N₅ OS 1/3H₂ O;requires: C, 48.3; H, 6.5; N, 25.6; S, 11.7).

EXAMPLE 125,5-Dimethyl-2-[2-(4-methyl-5-imidazolylmethylthio)-ethylamino]-2-imidazolin-4-one

5,5-Dimethyl-2-thiohydantoin (14.4 g.) was converted to2-methylthio-5,5-dimethyl-2-imidazolin-4-one hydroiodide (17.4 g., m.p.187°-189°) according to the method described in Example 11. A solutionof this hydroiodide (5.7 g.) and4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (6.85 g.) in dryethanol (45 ml.) was left to stand at room temperature for 4 days. Thereaction mixture was evaporated to dryness and the residuerecrystallised from water to give5,5-dimethyl-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]-2-imidazolin-4-one(3.1 g.) m.p. 232°-236°. Further recrystallisation from water gave ananalytical sample, m.p. 235°-7°.

(Found: C, 50.9; H, 6.9; N, 24.8; S, 11.4; C₁₂ H₁₉ N₅ OS; requires: C,51.2; H, 6.8; N, 24.9; S, 11.4).

EXAMPLE 135-Benzyl-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one

5-Benzyl-2-thiohydantoin was converted to2-methylthio-5-benzyl-2-imidazolin-4-one hydroiodide (m.p. 192°-194°)according to the method described in Example 11.

A solution of this hydroiodide (2.5 g.),4(5)-(2-aminoethyl)-thiomethyl-5(4)-methylimidazole (1.9 g.) andtriethylamine (0.74 g.) in dry ethanol (15 ml.) was left to stand atroom temperature for 4 days. The reaction mixture was evaporated todryness, the residue dissolved in isopropanol (25 ml.) and the resultingsolution poured into ether (200 ml.) to give5-benzyl-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one(1.23 g.) m.p. 104°-7°.

EXAMPLE 142-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]pyrimid-4-thionedihydrochloride

A mixture of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone (5 g.)and phosphorus pentasulphide (4 g.) in pyridine (150 ml.) was heatedunder reflux, with stirring, for 2 hours. The reaction mixture wasevaporated to dryness, boiled with water for 30 minutes and againevaporated to dryness. The residue was dissolved in dilute ammoniumhydroxide, the solution washed with chloroform and the aqueous layerevaporated to dryness. Concentrated hydrochloric acid was added to theresidue to give a pale yellow solid, which was dissolved in warm water,filtered, and the filtrate acidified with concentrated hydrochloric acidto give2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]pyrimid-4-thionedihydrochloride, m.p. 245°-247°.

(Found: C, 37.0; H, 4.9; N, 19.55; S, 17.7; C₁₁ H₁₇ Cl₂ N₅ S₂ ;requires: C, 37.3; H, 4.8; N, 19.8; S, 18.1.).

EXAMPLE 152-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-6-one

A mixture of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (20 g.)and 2-bromo-6-ethoxy-pyridine (11.9 g.) was heated with stirring at 160°for 4 hours. After cooling, the reaction mixture was dissolved in 20%aqueous hydrobromic acid and the solution extracted with ether torecover unchanged 2-bromo-6-ethoxypyridine. The aqueous layer wasbasified with potassium carbonate, extracted with chloroform and thecombined extract washed with water and dried (MgSO₄). After removal ofthe chloroform the residue was chromatographed on silica gel, elutingwith first ethyl acetate to remove impurities and then ethylacetate/methanol/chloroform (4:1:2) to elute the required product.Evaporation of the eluate gave2-ethoxy-6-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]pyridine as anoil, which on treatment with a solution of picric acid in ethanol gavethe dipicrate, m.p. 172°.

A solution of this ethoxypyridine (3.4 g. of base) in 5N hydrochloricacid (100 ml) was heated under reflux for 21/2 hours. The reactionmixture was evaporated to dryness, the residue dissolved in a minimumamount of water, the solution basified with aqueous potassium carbonate,washed once with chloroform, and allowed to stand at 0° overnight.Crystals of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-6-one werecollected and recrystallised from water to give the pure product, m.p.85°.

(Found: C, 54.25; H, 6.0; N, 20.9; S, 11.9; C₁₂ H₁₆ N₄ OS; requires: C,54.5; H, 6.1; N, 21.2; S, 12.1)

EXAMPLE 162-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one

A mixture of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (7.6 g.)and 2-bromo-4-pyridone (3.8 g.) was heated with stirring at 160° for 3hours. After cooling, the reaction mixture was chromatographed on silicagel, eluting with first ethyl acetate isopropanol (5:1) to removeunreacted 2-bromo-4-pyridene and then isopropanol/ethanol (5:1) toremove the product. After evaporation of the combined eluates theresidue was purified further by ion-exchange chromatography using IRA400 (OH form) resin and eluting first with water to remove unchangedamine and then IN hydrochloric acid to remove the product. Evaporationof the acid fractions and recrystallisation of the residue fromisopropanol/ethyl acetate gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one, m.p.208°-210°.

EXAMPLE 173-[2-((4-Methyl-5-imidazolylmethylthio)ethyl)amino]-1,2,4-benzothiadiazine-1,1-dioxide

A mixture of 3-methylmercapto-1,2,4-benzothiadiazine-1,1-dioxide (5.58g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.20 g.) washeated at 140°-150° for 2 hours and then cooled. Following dissolutionin ethanol, and cooling the crude product was obtained as a solid (5.67g.) which was recrystallized from water and then methanol to give3-[2-((4-methyl-5-imidazolylmethylthio)ethyl)amino]-1,2,4-benzothiadiazine-1,1-dioxide(4.30 g.), m.p. 194.5°-196°.

(Found: C, 48.0; H, 5.0; N, 19.8; S, 18.2; C₁₄ H₁₇ N₅ O₂ S₂ ; requires:C, 47.8; H, 4.9; N, 19.9; S, 18.3).

EXAMPLE 183-[2-((4-Methyl-5-imidazolyl)methylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide

A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) washeated in an oil bath at 140° for 4 hours. The product waschromatographed on a column of silica gel with ethyl acetate-ethanol(3:2) as eluant and finally recrystallised from ethanol-ether to give3-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide(2.2 g.) m.p. 146°-147°.

(Found: C, 39.6; H, 6.0; N, 22.9; C₁₀ H₁₇ N₅ O₂ S₂ ; requires: C, 39.6;H, 5.7; N, 23.1)

EXAMPLE 194-[2-((4-Methyl-5-imidazolylmethylthio)ethylamino]thianoline-2-one

A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.71 g.)and thiazolidine-2-one-4-thione (1.33 g.) in methanol (30 ml.) washeated under reflux for one hour. Concentration, followed by successiverecrystallisation of the residue from methanol, ethanol and aqueousethanol afforded4-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]thiazoline-2-one (1.0g.) m.p. 195°-197°.

(Found: C, 44.2; H, 5.1; N, 20.5; S, 23.6; C₁₀ H₁₄ N₄ OS₂ ; requires: C,44.4; H, 5.2; N, 20.7; S, 23.7).

EXAMPLE 203-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-1,2,4-triazin-2H-5-one.

An intimate mixture of 3-methylthio-6-methyl-1,2,4-triazin-2H-5-one(7.64 gms) and 5-(2-aminoethyl)thiomethyl-4-methylimidazole (8.75 gms)was heated slowly to 160° C. and maintained at this temperature for onehour. After cooling the resulting solid was dissolved in 2N.HCl (100ml), filtered and the filtrate basified with aqueous K₂ CO₃ solution.The resulting precipitate was collected, washed with water, dried andextracted in a Soxhlet extractor with methanol for 16 hours. Themethanol solution was cooled giving yellow-buff crystals.Re-crystallisation from dimethylsulphoxide gave3-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-1,2,4-triazin-2H-5-one(7.8 gms.), m.p. 264°-266° C. (Dec).

(Found: C, 46.8; H, 5.7; N, 29.9; S, 12.0; C₁₁ H₁₆ N₆ OS; requires: C,47.1; H, 5.7; N, 30.0; S, 11.44).

EXAMPLE 213-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-1,2,4-triazin-2H-5-one

An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methyl imidazole(8.6 gms) and 3-methylthio triazin-2H-5-one (6.68 gms) was slowly heatedto 120° C. and kept at this temperature for four hours. After coolingthe resulting solid was recrystallised twice from n-propanol and twicefrom water to give3-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-1,2,4-triazin-2H-5-one,m.p. 238°-238.5° C.

(Found: C, 45.1; H, 5.55; N, 31.5; S, 11.9; C₁₀ H₁₄ N₆ OS; requires: C,45.1; H, 5.3; N, 31.6; S, 12.0).

EXAMPLE 222-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone

5-Benzyl-6-methylthiouracil (6.0 gms) and sodium hydroxide (1.06 gms)were dissolved in water (30 mls). The solution was cooled and ethanol(60 mls) and methyl iodide (3.67 gms) added with stirring. The mixturewas heated at 60° C. for 1/2 hour, cooled and the resulting solidcollected and water-washed. A second crop of solid was obtained byacidification of the filtrate to pH=4 with acetic acid.Recrystallisation from ethanol produced5-benzyl-6-methyl-2-methylthio-4-pyrimidone (5.53 gms) m.p.=220°-221.5°C.

An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole(1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms)was heated at 150°-160° C. (oil-bath temperature) for 41/2 hours. Themixture was cooled, washed with water and recrystallised fromisopropanol to give2-[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone(1.82 gms) m.p.=140°-141.5° C.

(Found: C, 61.7; H, 6.6; N, 18.5; S, 8.20; C₁₉ H₂₃ N₅ OS; requires: C,61.8; H, 6.3; N, 18.95; S, 8.68).

EXAMPLE 23 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone

2-Chloro-4-ethoxyquinoline (3.72 gms) and5-(2-aminoethyl)thiomethyl-4-methylimidazole (3.1 g.) were heatedtogether at 150°-160° C. (oil-bath temperature) for three hours. Theresidue, on colling, was washed with water and dried. Purification waseffected by column chromatography (silica gel column, ethyl acetate-5%methanol eluant) and crystallisation from acetone to give2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline(1.86 gms) m.p.=152.5°-153.5° C.

(Found: C, 63.2; H, 6.5; N, 16.1; S, 9.1; C₁₈ H₂₂ N₄ OS; requires: C,63.1; H, 6.5; N, 16.4; S, 9.4).

2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline(1.69 gms) and concentrated HCl (30 mls) were refluxed together for 17hours. The solution was evaporated to dryness, the residue dissolved inwater and basified with potassium carbonate. The precipitated oil wasseparated by decantation, washed with water and crystallised fromisopropanol-water to give2[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-quinolonem.p.=121°-124° C.

(Found: C, 60.1; H, 5.7; N, 17.1; S, 9.9; C₁₆ H₁₈ N₄ OS; requires; C,61.1; H, 5.8; N, 17.8; S, 10.2).

EXAMPLE 24 4-[4-(4-Imidazolyl)butylamino]-2-thiopyrimidone

Reaction of 4(5)-(4-aminobutyl)imidazole (2.8 g.) with2,4-dimercaptopyrimidine (1.44 g.) by the method described in Example 5gave 4-[4-(4-imidazolyl)butylamino]-2-thiopyrimidone, m.p. 209°-211° (exn-propanol).

(Found: C, 51.4; H, 6.3; N, 27.0; S, 13.0; C₁₁ H₁₅ N₅ S. 0.4 H₂ O.requires: C, 51.6; H, 6.3; N, 27.35; S, 12.5).

EXAMPLE 25

Reaction of 2-methylthio-4-pyrimidone by the procedure of Example 1 withthe following compounds:

4-[(2-aminoethyl)thiomethyl]imidazole

4-(2-aminoethyl)thiomethyl-5-bromoimidazole

4-[(3-aminopropyl)thiomethyl]imidazole

2-(2-aminoethyl)thiomethyl-3-bromopyridine

2-(2-aminoethyl)thiomethyl-3-hydroxypyridine

2-(2-aminoethyl)thiomethyl-3-methylpyridine

2-(2-aminoethyl)thiomethyl-3-aminopyridine

2-[(2-aminoethyl)thiomethyl]thiazole

2-(4-aminobutyl)thiazole

3-[(2-aminoethyl)thiomethyl]isothiazole

3-(2-aminoethyl)thiomethyl-4-bromoisothiazole

2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole

4-(5-aminopentyl)imidazole

yields the following products:

2-[2-(4-imidazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(4-bromo-5-imidazolylmethylthio)ethylamino]-4-pyrimidone

2-[3-(4-imidazolylmethylthio)propylamino]-4-pyrimidone

2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-methyl-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-amino-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(2-thiazolylmethylthio)ethylamino]-4-pyrimidone

2-[4-(2-thiazolyl)butylamino]-4-pyrimidone

2-[2-(3-isothiazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(4-bromo-3-isothiazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethylamino]-4-pyrimidone

.2-[5-(4-imidazolyl)pentylamino]-4-pyrimidone

EXAMPLE 262-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-phenyl-6-methyl-4-pyrimidone

When 5-phenyl-6-methylthiouracil is used as the starting material in theprocedures of Example 22 the title compound, m.p.=215.5°-217.5° C., isproduced.

EXAMPLE 27

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        2-[2-(4-methyl-5-imidazolylmethylthio)-                                                                 150    mg                                           ethylamino]-4-pyrimidone                                                      Sucrose                   75     mg                                           Starch                    25     mg                                           Talc                      5      mg                                           Stearic Acid              2      mg                                           ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 28

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        2-[2-(4-Methyl-5-imidazolylmethylthio)-                                                                200 mg                                               ethylamino]-5-benzyl-6-methyl-4-pyrimidone                                    Lactose                  100 mg                                               ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule

What we claim is:
 1. A method of inhibiting H-2 histamine receptors,said H-2 histamine receptors being those histamine receptors which arenot inhibited by mepyramine but are inhibited by burimamide, whichcomprises administering to an animal in need of inhibition of saidreceptors in an effective amount to inhibit said receptors aheterocyclic compound of the formula: ##STR4## wherein A taken togetherwith the nitrogen and carbon atoms show forms a pyridine ring, said ringhaving a keto or thione group and optionally substituted by one or twolower alkyl, phenyl or benzyl groups; R is a grouping of the formula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is a nitrogen containing heterocyclic ring selected frompyridine, thiazole, isothiazole or thiadiazole, said ring beingoptionally substituted by lower alkyl, amino, hydroxy or halogen; Z issulphur or a methylene group and n is 2 or 3 or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A method of claim 1 in whichthe heterocyclic compound is administered in a daily dosage of fromabout 150 mg. to about 750 mg.
 3. A method of inhibiting gastric acidsecretion which comprises administering internally to an animal in needof inhibition of gastric acid secretion in an effective amount toinhibit gastric acid secretion a heterocyclic compound of the formula:##STR5## wherein A taken together with the nitrogen and carbon atomsshown forms a pyridine ring, said ring having a keto or thione group andoptionally substituted by one or two lower alkyl, phenyl or benzylgroups; R is a group of the formula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is a nitrogen containing heterocyclic ring selected frompyridine, thiazole, isothiazole or thiadiazole, said ring beingoptionally substituted by lower alkyl, amino, hydroxy or halogen; Z issulphur or a methylene group and n is 2 or 3 or a pharmaceuticallyacceptacle acid addition salt thereof.
 4. A pharmaceutical compositionto inhibit H-2 histamine receptors, said H-2 histamine receptors beingthose histamine receptors which are not inhibited by mepyramine but areinhibited by burimamide, comprising a pharmaceutical carrier and in aneffective amount to inhibit said receptors a heterocyclic compound ofthe formula: ##STR6## wherein A taken together with the nitrogen andcarbon atoms shown forms a pyridine ring, said ring having a keto orthione group and optionally substituted by one or two lower alkyl,phenyl or benzyl groups; R is a grouping of the formula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is a nitrogen containing heterocyclic ring selected frompyridine, thiazole, isothiazole or thiadiazole, said ring beingoptionally substituted by lower alkyl, amino, hydroxy or halogen; Z issulphur or a methylene group and n is 2 or 3 or a pharmaceuticallyacceptable acid addition salt thereof.
 5. A pharmaceutical compositionof claim 4 in which the heterocyclic compound is present in an amount offrom about 50 mg to about 250 mg.